In the course of evolution, many organisms tackled the task of introducing macromolecules into living cells. Aside from the cell-specific, usually receptor-mediated or active uptake mechanisms, the general solution that has independently emerged in many lineages relies on peptides specifically evolved to interact with, and insert into lipid bilayer membranes. Thus, bacterial colicins, human porins, and protein transduction domains (PTDs) from diverse species share the motif of a positively charged alpha-helix, frequently with an amphipathic structure, which is capable of inserting into lipid membranes, and delivering larger cargoes intracellularly. Recent research reports confirm the successful use of PTDs fused to proteins for their delivery across biological boundaries, including the blood-brain barrier, and the placenta.
Mitochondria are the α-proteobacterial, energy producing and cell death controlling endosymbionts in all eukaryotic cells (Fitzpatrick, et al., Mol Biol Eva, 23(1):74-85 (2006)). The mitochondrial outer membrane has a lipid composition similar to that of eukaryotic plasma membranes, whereas the mitochondrial inner membrane contains a unique lipid, cardiolipin, and more closely resembles bacterial membranes. Mitochondria contain their own DNA, transcription and translation machinery, involved in producing proteins necessary to carry out oxidative phosphorylation. Many diseases are associated with a decline in mitochondrial number, mitochondrial function, or more specifically, oxidative phosphorylation. Furthermore, increasing mitochondrial function, number and/or oxidative phosphorylation in a basal or healthy state may increase the capabilities of cells and tissues heavily reliant on mitochondrial metabolism, such as brain and muscle.
Therefore it is an object of the invention to provide compositions and methods for increasing mitochondrial number, mitochondrial function and/or oxidative phosphorylation in a subject.